Submissions for variant NM_000030.3(AGXT):c.242C>T (p.Ser81Leu)

gnomAD frequency: 0.00001  dbSNP: rs180177184

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001386863	SCV001587247	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 81 of the AGXT protein (p.Ser81Leu). This variant is present in population databases (rs180177184, gnomAD 0.007%). This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 20564000, 24988064). ClinVar contains an entry for this variant (Variation ID: 204083). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AGXT protein function. Experimental studies have shown that this missense change affects AGXT function (PMID: 24990153). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271450	SCV002556310	pathogenic	Primary hyperoxaluria	2022-06-03	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.242C>T (p.Ser81Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251240 control chromosomes (gnomAD). The variant, c.242C>T, has been reported in the literature in compound heterozygous individuals affected with Primary Hyperoxaluria Type 1(Montioli_2014, Williams_2009, Mandrile_2014); the variant was noted to be found on the major allele, and was described to be associated with an earlier onset of end-stage renal disease (ESRD) when it occurred in trans with a null mutation, compared to when occurring in trans with the p.G170R mutation (Montioli_2014, Mandrile_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant didn't affect the expression level of the protein, however, it resulted in a severely decreased pyridoxal phosphate binding, with less than ~5% residual activity in the absence of PLP, while in the presence of PLP the specific activity was ~20% of the WT (Montioli_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000186289	SCV002801345	likely pathogenic	Primary hyperoxaluria, type I	2021-12-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001386863	SCV004011317	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	AGXT: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186289	SCV000239618	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	research